Angiotensin-converting enzyme inhibitors: An ACE in the hole for everyone?

Issue: BCMJ, vol. 53 , No. 5 , June 2011 , Clinical Articles

Angiotensin-converting enzyme inhibitors (ACEIs) are commonly used to treat cardiovascular disorders. The use of ACEIs for hypertension is well established, although these agents have not proven to be superior to other antihypertensive agents. The use of ACEIs in heart failure is also well established, and has proven to reduce morbidity and mortality. ACEIs are now routinely used in myocardial infarction patients to reduce reinfarction and mortality risk, and are combined with a diuretic for secondary prevention in stroke patients. Proof that ACEIs also re­duce the progression of diabetic neph­ro­pathy supports their use in all diabetic patients. With the evidence of efficacy now available, angiotensin-converting enzyme inhibitors should be considered for all patients with diabetes or a history of cardiovas­cular disease, except for those at low risk.

 


Numerous trials have confirmed that patients with hypertension and other compelling indications (heart failure, diabetes, stroke, and myocardial infarction) can benefit from first-line therapy with ACEIs.


The use of angiotensin-converting enzyme inhibi­tors (ACEIs) is ubiquitous in the treatment of cardiovascular disorders. These agents inhibit the action of the angiotensin-converting enzyme that catalyzes the conversion of angiotensin I to angio­tensin II, a potent vasoconstrictor.

Inhibition of angiotensin II results in vasodilation, reduced sodium retention, and reduced sympathetic and renin-angiotensin-aldosterone system activation. There is considerable evidence available supporting the use of ACEIs in patients with hypertension, heart failure, and myocardial infarction (MI), and for prevention of secondary stroke, cardiovascular events, and diabetic nephropathy. 

ACEIs are considered contraindicated in patients with hyperkalemia, previous angio­edema with ACEIs, pregnant patients, and patients with bilateral renal artery stenosis.

Hypertension
Several clinical trials have shown that ACEIs are effective agents in the treatment of hypertension; however, these trials have not shown ACEIs to be superior to other antihypertensives in the absence of compelling indications (e.g., heart failure, diabetes, myocardial infarction). 

Three large, landmark studies investigating ACEI use in hypertension are the ALLHAT, the CAPPP trial, and the UKPDS.[1-3

The ALLHAT compared lisinopril with conventional therapy (chlorthalidone or amlodipine). The CAPPP trial compared captopril with conventional therapy (beta-blocker or diuretic), while the UKPDS compared captopril with atenolol. 

All three trials concluded that ACEIs are not superior to conventional therapy designed to treat uncomplicated hypertension in order to reduce risk of myocardial infarction, stroke, or cardiac death. Thus, for uncomplicated hypertension, an ACEI is one option among the various antihypertensive drug classes. 

If hyper­tension is accompanied by other compelling indications (previous stroke, diabetes, heart failure, myocardial in­farction), then an ACEI is strongly recommended as the first-line anti­hypertensive therapy. This is supported by the most recent Joint National Committee hypertension guidelines (JNC 7 report) as well as by the 2010 Canadian Hypertension Education Program (CHEP) guidelines.[4,5]

Heart failure 
Clinical trials uniformly show that ACEIs reduce all-cause mortality in patients with varying degrees of heart failure. The initial trials of ACEI use in heart failure patients consistently showed significant reduction in mortality.[6,7

More recent trials (the AIRE and TRACE studies) have also shown mortality reduction with ramipril and trandolapril.[8,9] These landmark trials all demonstrated a mortality reduction with ACEI use when compared with placebo. 

The 2009 American College of Cardiology/American Heart Association (ACC/AHA) guidelines and 2006 Canadian consensus guidelines strongly recommend ACEI use in all heart failure patients with a reduced left ventricular ejection fraction (LVEF) of 40% or less to reduce mortality and worsening heart function.[10,11]

Current guidelines recommend the uptitration of an ACEI to achieve target doses or the highest dose tolerated by the pa­tient. Optimal dosing of an ACEI in heart failure patients has been assoc­iated with decreased risk of hospitalization.

Myocardial infarction
Several studies demonstrate that the use of an ACEI in patients recovering from an MI results in a significant reduction in all-cause mortality and morbidity. Landmark trials (CCS-1, GISSI-3, and SMILE) all uniformly demonstrated a mortality reduction when ACEI therapy was used after an MI.[12-14

More recent trials (the TRACE and AIRE studies) also dem­onstrated mortality reduction with ACEI use, particularly in patients with left ventricular dysfunction.8,9 A meta-analysis of all published, major trials investigating the use of an ACEI after an MI conclusively supports a role for ACEI therapy in the early phase and ongoing management of MI.[15

The 2004 ACC/AHA guidelines for ST-elevation MI strongly recommend the use of an ACEI for all patients to reduce mortality.[16] However, for low-risk MI patients, the use of an ACEI is also reasonable and may be considered.[17]
 
Secondary stroke prevention
There have been only two studies investigating the role of an ACEI in secondary stroke prevention. The PROGRESS trial compared the use of perindopril and indapamide (in combination) versus perindopril alone versus placebo in patients with a history of stroke or transient ischemic attack.[18

The trial demonstrated a benefit for ACEI therapy (perindopril) only when used in conjunction with a diuretic (indapamide). In the HOPE trial, ramipril demonstrated a significant reduction in the composite endpoint of death, MI, and stroke compared with placebo in a population at high risk of cardiac events.[19

Because a composite outcome was involved, it is not completely clear if ACEI therapy alone reduces the incidence of a second stroke, even though the evidence suggests benefits for ACEI therapy. The latest ACC/AHA guidelines for secondary stroke prevention recommend the use of a thiazide or thiazide combined with an ACEI for secondary stroke prevention.[20]
 
Increased risk for cardiovascular events
The use of an ACEI in patients at high risk for cardiovascular events is commonplace and has been investigated in three large clinical trials. The HOPE trial was conducted in a population with documented coronary artery disease (CAD) or diabetes and additional cardiac risk factors and a normal LVEF.[19

The use of ramipril versus placebo in this study demonstrated a reduction in a composite end point of death, MI, and stroke. The results of HOPE supported the use of ACEI in all patients at high risk for cardiovascular events. Similar to HOPE, EUROPA showed that use of perindopril decreased cardiovascular events in high-risk CAD patients.[20

The PEACE trial studied high-risk CAD patients treated with trandolapril versus placebo.[21] The results of PEACE showed no benefit of trandolapril over placebo in reducing cardiovascular events, which conflicts with previous studies. It is thought that the results of the PEACE trial might be attributed to the fact that the majority of patients were medically optimized and a significant percentage of them were revascularized, unlike the patients in the HOPE study. 

Thus, in patients at high risk of cardiovascular events, ACEI is recommended. The 2006 AHA/ACC guidelines state that ACEIs should be used in all patients with high cardiovascular risk, but should be considered as optional in patients at low cardiovascular risk.[17]

Diabetic nephropathy
The literature and a few large studies show a benefit for ACEI use in slowing the progression of diabetic neph­ro­pathy. The two largest trials of an ACEI in diabetic nephropathy are the HOPE-MICRO subgroup analysis and the BENEDICT, which both found a benefit based on surrogate markers.[22,23

In the HOPE-MICRO subgroup study, use of ramipril in diabetic patients reduced the incidence of overt nephropathy (defined as proteinuria). The BENEDICT study dem­onstrated that trandolapril (versus placebo) reduced the incidence of microalbuminuria in diabetic patients. 

The 2008 Canadian Diabetes Guidelines and 2010 American Diabetes Guidelines both strongly recommend therapy with either an ACEI or an angiotensin-receptor blocker (ARB) in diabetic patients to prevent diabetic nephropathy.[24,25]

Conclusions
ACEIs have demonstrated clinical benefits when used in a wide range of cardiovascular disorders. ACEI use reduces mortality after an MI and in heart failure, and are now routinely used in all patients. ACEIs are an option in the treatment of hypertension, but are no more effective than conventional therapies in uncomplicated cases of hypertension. 

ACEIs show benefit in secondary stroke prevention, but only when combined with a diuretic. An ACEI should be used in all diabetic patients to reduce the incidence of diabetic nephropathy. ACEI therapy is considered optional in pa­tients at low risk for a cardiovascular event and in patients without compelling indications.

ACEIs are considered contraindicated in patients with hyperkalemia, previous angioedema with ACEIs, pregnant patients, and patients with bilateral renal artery stenosis.

Competing interests
None declared.

This article has been peer reviewed.


References

1. ALLHAT Officers and Coordinators for the ALLHAT Collaborative Research Group. Major outcomes in high-risk hypertensive patients randomized to angiotensin-converting enzyme inhibitor or calcium channel blocker vs diuretic: The Antihypertensive and Lipid-Lowering Treatment to Prevent Heart Attack Trial. JAMA 2002;288:2981-2997.
2. Hansson L, Luomanmaki K, Dahlof B, et al. Effect of angiotensin-converting en­zyme inhibition compared with conventional therapy on cardiovascular morbidity and mortality in hypertension: The Captopril Prevention Project (CAPPP) randomised trial. Lancet 1999;353(9153):611-616.
3. Efficacy of atenolol and captopril in reducing risk of macrovascular and microvascular complications in type 2 diabetes: UKPDS 39. UK Prospective Diabetes Study Group. BMJ 1998;317:713-720.
4. Chobanian AU, Bakris GL, Black HR, et al. The Seventh Report of the Joint Na­tional Committee on Prevention, Detection, Evaluation, and Treatment of High Blood Pressure: The JNC 7 report. JAMA 2003;289:2560-2572
5. Campbell NR, Kaczorowski J, Lewanc­zuk RZ, et al. 2010 Canadian Hypertension Education Program (CHEP) recommendations: The scientific summary—an update of the 2010 theme and the science behind new CHEP recommendations. Can J Cardiol 2010;26:236-240.
6. Effect of enalapril on survival in patients with reduced left ventricular ejection fractions and congestive heart failure. The SOLVD Investigators. N Engl J Med 1991;325:293-302.
7. Pfeffer MA, Braunwald E, Moye LA, et al. Effect of captopril on mortality and morbidity in patients with left ventricular dysfunction after myocardial infarction. Results of the survival and ventricular enlargement trial. The SAVE Investigators. N Engl J Med 1992;327:669-677.
8. Effect of ramipril on mortality and morbidity of survivors of acute myocardial infarction with clinical evidence of heart failure. The Acute Infarction Ramipril Efficacy (AIRE) Study Investigators. Lancet 1993;342(8875):821-828.
9. Kober L, Torp-Pedersen C, Carlsen JE, et al. A clinical trial of angiotensin-converting enzyme inhibitor trandolapril in patients with left ventricular dysfunction after myocardial infarction. Trandolapril Cardiac Evaluation (TRACE) Study Group. N Engl J Med 1995;333:1670-1676.
10. Hunt SA, Abraham WT, Chin MH, et al. 2009 Focused update incorporated into the ACC/AHA 2005 guidelines for the diagnosis and management of heart failure in adults. Circulation 2009;119:e391-e479.
11. Arnold JM, Liu P, Demers C, et al. Canadian Cardiovascular Society consensus conference recommendations on heart failure 2006: Diagnosis and management. Can J Cardiol 2006;22:23-45.
12. Oral captopril vs placebo among 13,634 patients with suspected acute myocardial infarction: Interim report from the Chinese Cardiac Study (CCS-1). Lancet 1995;345(8961):686-687.
13. GISSI-3: Effects of lisinopril and transdermal glyceryl trinitrate singly and together on 6-week mortality and ventricular function after acute myocardial infarction. Gruppo Italiano per lo Studio della Sopravviuenza nell’infarto Miocardico. Lancet 1994;343:1115-1122.
14. Ambrosioni E, Borhi C, Magnani B, et al. The effect of the angiotensin-converting enzyme inhibitor zofenopril on mortality and morbidity after anterior myocardial infarction. The Survival of Myocardial Infarction Long-Term Evaluation (SMILE) Study Investigators. N Engl J Med 1995;332:80-85.
15. Latini R, Maggioni AP, Flather M, et al. ACE inhibitor use in patients with myo­cardial infarction: Summary of evidence from clinical trials. Circulation 1995;92:3132-3137.
16. Antman EM, Anbe DT, Armstrong PW, et al. ACC/AHA guidelines for the management of patients with ST-elevation myocardial infarctions: A report of the American College of Cardiology/American Heart Association task force on practice guidelines (Committee to revise the 1999 guidelines for the management of patients with acute myocardial infarction). J Am Coll Cardiol 2004;44:E1-E211
17. Smith SC, Allen J, Blair SN, et al. AHA/ACC guidelines for secondary prevention for patients with coronary and other atherosclerotic vascular disease: 2006 update. J Am Coll Cardiol 2006;47:2130-2139.
18. Randomised trial of a perindopril-based blood-pressure-lowering regimen among 6,105 individuals with previous stroke or transient ischaemic attack. PROGRESS Collaborative Group. Lancet 2001;358(9287):1033-1041.
19. Effects of an angiotensin-converting enzyme inhibitor, ramipril on cardiovascular events in high-risk patients. The Heart Outcomes Prevention Evaluation Study Investigators. N Engl J Med 2000;342:145-153.
20. Fox KM; EURopean trial On reduction of cardiac events with Perindopril in stable coronary Artery disease investigators. Efficacy of perindopril in reduction of cardiovascular events among patients with stable coronary artery disease: Random­ised double-blind, placebo-controlled, multicentre trial (the EUROPA study). Lancet 2003;362(9386):782-788.
21. Braunwald E, Domanski MJ, Fowler SE, et al.; PEACE Trial Investigators. Angiotensin-converting enzyme inhibition in stable coronary artery disease. N Engl J Med 2004;351:2058-2068.
22. Effects of ramipril on cardiovascular and microvascular outcomes in people with diabetes mellitus: Results of HOPE study and MICRO-HOPE substudy. HOPE Study Investigators. Lancet 2000;355(9200):253-259.
23. Rugganenti P, Fassi A, Ilieva AP, et al. Bergamo Nephrologic Diabetes Complications Trial (BENEDICT) Investigators. Preventing microalbuminuria in type 2 diabetes. N Engl J Med 2004;351:1941-1951.
24. Canadian Diabetes Association 2008 clinical practice guidelines for the prevention and management of diabetes in Canada. Can J Diabetes 2008;32:S1-S201.
25. American Diabetes Association clinical practice recommendations 2010. Diabetes Care 2010;33:S1-S99.


Dr Chua is a clinical pharmacy specialist at St. Paul’s Hospital in Vancouver. Dr Ignas­zewski is head of the Division of Cardiology at St. Paul’s Hospital. Ms Schwenger is a candidate in the Doctor of Pharmacy Program at the University of British Columbia.

Doson Chua, PharmD, BCPS(AQ),, Andrew Ignaszewski, MD, FRCPC, Erin Schwenger, BSc(Pharm),. Angiotensin-converting enzyme inhibitors: An ACE in the hole for everyone?. BCMJ, Vol. 53, No. 5, June, 2011, Page(s) - Clinical Articles.



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